Investigation has focused on the mechanism of regulation of hypothalamic and pituitary function during stress. Studies during cold stress show transient increases in plasma ACTH and sustained increases in corticosterone, similar to the responses to immobilization stress. In contrast to immobilization, CRH receptors were unchanged in the anterior pituitary, but markedly increased in the intermediate lobe. Cold-stressed rats showed plasma levels of the intermediate pituitary peptide, CLIP, similar to controls, but reduced responses to CRH injection, despite the increase in CRH receptors. Plasma ACTH responses to CRH injection in cold exposed rats were similar to those in controls, but the response to 5 min ether exposure was enhanced, indicating that hypersensitivity to a novel stress depends upon hypothalamic release of additional factors that synergise the effect of CRH. Cold-stressed rats showed larger decreases in CRH content in the median eminence following either stress, indicating the hypersensitivity of the hypothalamic response during chronic stress. Studies on the dopaminergic regulation of the intermediate pituitary showed time dependent increases in CRH receptor concentration, despite marked cellular atrophy and decreases in POMC mRNA levels. As during cold stress, CRH receptors upregulation was not accompanied by parallel functional changes. Studies were initiated to determine the regulation of hypothalamic release of CRH and VP, using immunohistochemical techniques. An new finding was that alpha-1 adrenergic receptors are important mediators of stress-induced CRH synthesis in the PVN and its release from the median eminence. Studies are in progress to elucidate the physiological role of the multiple neurotransmitters involved in the regulation of hypothalamic CRH and VP.